Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   42330   clinical trials with a EudraCT protocol, of which   6971   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .

    Clinical Trials marked as "Trial now transitioned" were transitioned to the Clinical Trial Regulation 536/2014 and can be further followed in the Clinical Trial Information System  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Randomized Multicenter Study Comparing Pixantrone + Rituximab with Gemcitabine + Rituximab in Patients with Aggressive B-cell Non-Hodgkin Lymphoma Who Have Relapsed after Therapy with CHOP-R or an Equivalent Regimen and are Ineligible for Stem Cell Transplant

    Summary
    EudraCT number
    2012-001790-86
    Trial protocol
    GB   ES   DE   FR   HU   IT   CZ   DK   BG   PL   BE   AT   SK   RO  
    Global end of trial date
    14 Sep 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Aug 2019
    First version publication date
    04 Aug 2019
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    PIX306
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01321541
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    CTI BioPharma Corp
    Sponsor organisation address
    3101 Western Avenue, Suite 800, Seattle, United States, 98121
    Public contact
    Ekaterina Efremova, PSI Company Ltd., , +7 812320 3855 0032, Ekaterina.Efremova@psi-cro.com
    Scientific contact
    Ekaterina Efremova, PSI Company Ltd., , +7 812320 3855 0032, Ekaterina.Efremova@psi-cro.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the efficacy (as measured by progression-free survival [PFS]) of pixantrone + rituximab compared with gemcitabine + rituximab in patients with a diagnosis of de novo diffuse large B-cell lymphoma (DLBCL), DLBCL transformed from indolent lymphoma, or follicular lymphoma (FL) Grade 3 who had relapsed after at least 1 prior chemotherapy regimen and who were currently ineligible for high-dose (myeloablative) chemotherapy and stem cell transplant (SCT). Sample size was based on the estimation that 195 PFS events (adjudicated by the Independent Radiology Committee [IRC]) were required to detect at least a 35% improvement (i.e., HR = 0.65) in PFS with 85% power and a 2-sided alpha of 0.05 (Amendments 8 & 9). For the secondary endpoint of overall survival (OS), it was planned to continue the study until 220 deaths had occurred (that required several months of follow-up after the core database lock for primary endpoint and first interim analysis of OS).
    Protection of trial subjects
    Patients were to give freely their written informed consent before their selection in the study. Informed consent to collect information on patient’s survival status was obtained from subjects at the time of enrolment. Patients were provided with updated information and re-consented if substantial changes in the study occurred due to study protocol amendments or new information about the study drug became available. This study was performed in accordance with Good Clinical Practice standards. Patient safety was monitored by an Independent Data Monitoring Committee (IDMC) whose responsibilities included: 1) minimization of the patients’ exposure to an unsafe therapy or dose, 2) evaluation of the toxicity and appropriateness of doses in both arms in order to make recommendations for changes in study, if appropriate, 3) advising on the need for dose adjustments because of safety issues, 4) any other safety associated assessments, including endorsing continuation of the study per protocol, and 5) providing the interim OS analyses and release of the unblinded OS results to the sponsor after all patients had completed study treatment.
    Background therapy
    Rituximab was administered in combination with both the investigational drug (pixantrone) and comparator drug (gemcitabine). Combining pixantrone chemotherapy with the anti-CD20 agent rituximab was expected to produce synergistic effects with minimal overlapping toxicity and minimal drug interactions.
    Evidence for comparator
    The choice of comparator (gemcitabine) was based on the National Comprehensive Cancer Network (NCCN) guidelines published at that time, for patients with relapsed or refractory DLBCL who are not candidates for SCT, recommending entry to a clinical study, or single-agent, doublet, or multiagent regimens, some containing gemcitabine and/or rituximab. The European Society of Medical Oncology (ESMO) guidelines also propose a gemcitabine-based regimen including rituximab as salvage treatment, or clinical trials with novel drugs, in patients non-eligible for transplant. Small studies have shown promising results in patients with relapsed or refractory DLBCL. The combination of gemcitabine and rituximab therefore appeared to be a reasonable therapeutic option in patients with relapsed non-Hodgkin lymphoma (NHL) if ineligible for SCT.
    Actual start date of recruitment
    01 Apr 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    United States: 102
    Country: Number of subjects enrolled
    Ukraine: 19
    Country: Number of subjects enrolled
    Russian Federation: 6
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Bulgaria: 24
    Country: Number of subjects enrolled
    Czech Republic: 28
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Italy: 31
    Worldwide total number of subjects
    312
    EEA total number of subjects
    183
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    66
    From 65 to 84 years
    233
    85 years and over
    13

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    The first patient, first visit was on 20 April 2011. The study was closed for enrolment in August 2017 when 312 patients had been randomized. Patients were randomized in North America (2 countries) and Europe (16 countries).

    Pre-assignment
    Screening details
    438 screened; 126 screen failures due to: inclusion/exclusion criteria not met (108), inclusion/exclusion criteria not met and other (4), consent withdrawn (4), inclusion/exclusion criteria not met and consent withdrawn (3), consent withdrawn and other (1), and other (6)

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Assessor [1]
    Blinding implementation details
    Treatment assignment was known to investigators, site personnel, and patients, but the sponsor (except certain sponsor personnel responsible for pharmacovigilance activities, regulatory submissions and GCP Compliance) and the IRC remained blinded during the study until core database lock. At the time of core database lock, the sponsor was unblinded to all data except the OS datasets. Deaths contributing to PFS events in the core locked database were part of the unblinded data.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Pixantrone + Rituximab
    Arm description
    Investigational therapy arm: The intent-to-treat (ITT) population included all 155 patients randomized to pixantrone + rituximab (pixantrone + R). The ITT population was used for analysis of demographic and baseline characteristics and efficacy. The safety population included all randomized patients who received at least one administration of study drug (153 patients); 2 patients were excluded from the safety population. The safety population was used for all safety analyses. 83 patients in the ITT population discontinued treatment due to: progressive disease (47), adverse event (21), consent withdrawal (6), death (5), or other reason (4).
    Arm type
    Experimental

    Investigational medicinal product name
    Pixantrone + Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pixantrone was supplied as a powder in a vial containing 50 mg pixantrone dimaleate equivalent to 29 mg pixantrone. Reconstitution to a solution containing pixantrone 5.8 mg/mL was done by adding 5 mL sterile 0.9% Sodium Chloride for Injection. Pixantrone was given in up to six 28-day cycles, consisting of pixantrone 50 mg/m^2 (in its base form) IV on Days 1, 8, and 15 of each cycle. Rituximab was a sterile, clear, colorless, preservative-free, liquid concentrate for IV administration. Rituximab was supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials. The necessary amount of rituximab was withdrawn and diluted to a final concentration of 1 to 4 mg/mL in an infusion bag containing either 0.9% Sodium Chloride or 5% Dextrose in water. Rituximab was given in up to six 28-day cycles at a dose of 375 mg/m^2 IV on Day 1 of each cycle. Rituximab was administered prior to pixantrone when both drugs were given on Day 1 of each cycle.

    Arm title
    Gemcitabine + Rituximab
    Arm description
    Control therapy arm: The intent-to-treat (ITT) population included all 157 patients randomized to gemcitabine + rituximab (gemcitabine + R). The ITT population was used for analysis of demographic and baseline characteristics and efficacy. The safety population included all randomized patients who received at least one administration of study drug (149 patients); 8 patients were excluded from the safety population. The safety population was used for all safety analyses. 96 patients discontinued treatment due to: progressive disease (50), adverse event (15), consent withdrawal (16), death (10), or other reason (5).
    Arm type
    Active comparator

    Investigational medicinal product name
    Gemcitabine + Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine was supplied as a lyophilized powder in vials containing 200 mg or 1 g gemcitabine. The powder was reconstituted to a solution containing gemcitabine 38 mg/mL by adding 5 mL or 25 mL of sterile 0.9% Sodium Chloride Injection without preservatives. Gemcitabine 1000 mg/m^2 was given IV in up to six 28-day cycles on Days 1, 8, and 15 of each cycle. Rituximab was a sterile, clear, colorless, preservative-free, liquid concentrate for IV administration. Rituximab was supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials. The necessary amount of rituximab was withdrawn and diluted to a final concentration of 1 to 4 mg/mL in an infusion bag containing either 0.9% Sodium Chloride or 5% Dextrose in water. Rituximab was given in up to six 28-day cycles at a dose of 375 mg/m^2 IV on Day 1 of each cycle. Rituximab was administered prior to gemcitabine when both drugs were given on Day 1 of each cycle.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Treatment assignment was known to investigators, site personnel, and patients, but the sponsor (except certain sponsor personnel responsible for pharmacovigilance activities, regulatory submissions and GCP Compliance) and the Independent Radiology Committee (IRC) remained blinded during the study until core database lock.
    Number of subjects in period 1
    Pixantrone + Rituximab Gemcitabine + Rituximab
    Started
    155
    157
    Completed treatment
    72
    61 [2]
    Completed
    52
    63
    Not completed
    103
    94
         Site closed; lack of compliance
    1
    -
         Physician decision
    1
    -
         Adverse event, serious fatal
    94
    84
         Consent withdrawn by subject
    6
    8
         Lost to follow-up
    1
    2
    Notes
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of patients who completed the study is greater than the number who completed treatment because patients who discontinued treatment entered the Follow-up periods (Early, Intermediate, and/or Survival) to be followed for safety and progression and/or survival. The number of patients who completed the study consists of patients who completed treatment and completed the study (i.e., the Follow-up period[s]) plus patients who discontinued treatment and completed the study.

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Pixantrone + Rituximab
    Reporting group description
    Investigational therapy arm: The intent-to-treat (ITT) population included all 155 patients randomized to pixantrone + rituximab (pixantrone + R). The ITT population was used for analysis of demographic and baseline characteristics and efficacy. The safety population included all randomized patients who received at least one administration of study drug (153 patients); 2 patients were excluded from the safety population. The safety population was used for all safety analyses. 83 patients in the ITT population discontinued treatment due to: progressive disease (47), adverse event (21), consent withdrawal (6), death (5), or other reason (4).

    Reporting group title
    Gemcitabine + Rituximab
    Reporting group description
    Control therapy arm: The intent-to-treat (ITT) population included all 157 patients randomized to gemcitabine + rituximab (gemcitabine + R). The ITT population was used for analysis of demographic and baseline characteristics and efficacy. The safety population included all randomized patients who received at least one administration of study drug (149 patients); 8 patients were excluded from the safety population. The safety population was used for all safety analyses. 96 patients discontinued treatment due to: progressive disease (50), adverse event (15), consent withdrawal (16), death (10), or other reason (5).

    Reporting group values
    Pixantrone + Rituximab Gemcitabine + Rituximab Total
    Number of subjects
    155 157 312
    Age categorical
    At baseline, most patients were 65 years old or older (78.8% overall). The median age of patients was 73.0 years ranging from 26 to 91 years. Age was well balanced between the treatment groups (p = 0.535).
    Units: Subjects
        Adults (18-64 years)
    36 30 66
        From 65-84 years
    113 120 233
        85 years and over
    6 7 13
    Age continuous
    Units: years
        median (full range (min-max))
    73 (30 to 91) 73 (26 to 90) -
    Gender categorical
    At baseline, just over half of the patients were women (56.4%). Gender was well balanced between the treatment groups (p = 0.819).
    Units: Subjects
        Female
    86 90 176
        Male
    69 67 136
    Region
    Two thirds of patients (66.7%) were enrolled in Europe and one third (33.3%) in North America. Region was well balanced between the treatment groups.
    Units: Subjects
        North America
    51 53 104
        Europe
    104 104 208
    Race
    The large majority (96.8%) of patients were white. Race was well balanced between the treatment groups (p = 0.165).
    Units: Subjects
        White
    147 155 302
        Black or African American
    4 1 5
        Asian
    1 1 2
        Other
    2 0 2
        Unknown
    1 0 1
    Histological subtype assessed by local investigators
    The most common histological subtype assessed by local investigators was DLBCL (77.6% of patients), 13.8% of patients had DLBCL transformed from indolent, and 8.7% had follicular lymphoma (FL) Grade 3 lymphoma. No relevant difference between the treatment groups was observed for this baseline disease characteristic (p = 0.644).
    Units: Subjects
        DLBCL
    122 120 242
        DLBCL transformed from indolent
    22 21 43
        FL Grade 3
    11 16 27
    Histology assessed by CPRC
    According to Central Pathology Review Committee (CPRC), 78.5% of patients had DLBCL, 4.8% had DLBCL with follicular components and 2.6% had FL Grade 3. Other patients were not diagnosed for lymphoma (4.8%), had other lymphoma (3.8%), were not assessed (3.5%) or assessment was missing (1.9%). No relevant difference between the treatment groups was observed for this baseline disease characteristic (p = 0.388).
    Units: Subjects
        DLBCL
    120 125 245
        DLBCL with follicular components
    5 10 15
        FL Grade 3
    3 5 8
        Non-diagnostic for lymphoma
    10 5 15
        Other lymphoma (none of the above)
    8 4 12
        Not assessed
    6 5 11
        Missing
    3 3 6
    Number of prior lines of therapy for DLBCL or FL Grade 3
    Most patients had received 1 prior therapy (61.9%) for DLBCL or FL Grade 3 lymphoma; 21.8% had received 2 prior therapies and 11.5% received 3 prior therapies. No relevant difference between the treatment groups was observed for this baseline disease characteristic (p = 0.823).
    Units: Subjects
        0 prior therapy
    9 6 15
        1 prior therapy
    93 100 193
        2 prior therapies
    35 33 68
        3 prior therapies
    18 18 36
    IPI Score
    Most patients (53.2%) had a baseline IPI score ≥ 3. No relevant difference between the treatment groups was observed for this baseline disease characteristic (p = 0.285).
    Units: Subjects
        Score = 0
    2 2
        Score = 1
    24 17 41
        Score = 2
    47 56 103
        Score >=3
    82 84 166
    Reason for ineligibility for HDC and SCT
    Main reason for non-eligibility for high-dose chemotherapy (HDC) and stem cell transplant (SCT) was “patient is not adequately fit” (39.4%). No relevant difference between the treatment groups was observed for this baseline disease characteristic (p = 0.579).
    Units: Subjects
        Patient is not adequately fit
    57 66 123
        Patient refused
    22 18 40
        Prior transplant
    16 12 28
        Co-morbid conditions
    11 15 26
        Failure to mobilize adequate number of cells
    2 2
        Other
    47 46 93
    ECOG PS
    Eastern Cooperative Oncology Group performance status (ECOG PS) at baseline was 0 for 27.2% of patients, 1 for 51.6% of patients, and 2 for 20.8% of patients; the score was missing for 1 patient (0.3%). No relevant difference was observed between the treatment groups for this baseline characteristic (p = 0.735).
    Units: Subjects
        Score = 0
    45 40 85
        Score = 1
    77 84 161
        Score = 2
    33 32 65
        Missing
    1 1
    Number of prior systemic therapies
    The treatment groups were comparable in regards to prior NHL therapy. Overall, more than half of the patients (54.8%) received one prior systemic therapy, 24.7% received 2 prior systemic therapies and 17.6% received 3 prior systemic therapies.
    Units: Subjects
        1 therapy
    83 88 171
        2 therapies
    39 38 77
        3 therapies
    29 26 55
        4 therapies
    4 5 9
    Type of the most recent systemic therapies
    The treatment groups were comparable in regards to prior NHL therapy. For the majority of patients (87.2%) the most recent systemic therapies for NHL prior to inclusion in the study pursued a curative intent.
    Units: Subjects
        Curative
    131 141 272
        Maintenance
    15 8 23
        Palliative
    5 5 10
        Other
    4 3 7
    Best response to the most recent systemic therapy
    The treatment groups were comparable in regards to prior NHL therapy. The best response to the most recent systemic therapy was complete response (CR) or complete response unconfirmed (CRu) in 55.4% of patients and PR in 30.1%.
    Units: Subjects
        Complete response/complete response unconfirmed
    83 90 173
        Partial response
    49 45 94
        Stable disease
    10 11 21
        Progressive disease
    11 9 20
        Unknown
    2 2 4
    Medical history - cardiac history
    Most patients presented with a cardiac history at baseline: 63.9% in the pixantrone + R group and 66.2% in the gemcitabine + R group.
    Units: Subjects
        Patients with any cardiac history events
    99 104 203
        Patients with no cardiac history events
    56 53 109
    Body Mass Index (BMI)
    At baseline, the mean BMI was 27.5 kg/m^2 ranging from 15 kg/m^2 to 62 kg/m^2. No relevant difference between the treatment groups was observed for BMI (p = 0.849).
    Units: kg/m^2
        arithmetic mean (full range (min-max))
    27.5 (15 to 62) 27.4 (16 to 48) -
    Time since initial diagnosis of DLBCL or FL Grade 3
    The initial diagnosis of DLBCL or FL Grade 3 was made at a median of 1.9 years (i.e. 22.8 months; ranging from 0 to 15 years) prior to study entry. No relevant difference between the treatment groups was observed for this baseline disease characteristic (p = 0.782).
    Units: years
        median (full range (min-max))
    1.8 (0 to 15) 2.0 (0 to 14) -
    Time from initiation of first-line therapy for DLBCL or FL Grade 3 until first relapse
    Time from initiation of first-line therapy for DLBCL or FL grade 3 until first relapse was a median of 1.4 years (i.e. 16.8 months). For pixantrone + rituximab, n = 144; for gemcitabine + rituximab, n = 151. No relevant difference between the treatment groups was observed for this baseline disease characteristic (p = 0.778).
    Units: years
        median (full range (min-max))
    1.4 (0 to 11) 1.4 (0 to 11) -
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population was defined as all randomized patients regardless of whether patients received any study treatment, or received a different treatment from the treatment they were randomized to. Patients were analyzed according to the treatment to which they were assigned at randomization. The ITT population consisted of all 312 patients randomized.

    Subject analysis sets values
    ITT population
    Number of subjects
    312
    Age categorical
    At baseline, most patients were 65 years old or older (78.8% overall). The median age of patients was 73.0 years ranging from 26 to 91 years. Age was well balanced between the treatment groups (p = 0.535).
    Units: Subjects
        Adults (18-64 years)
    66
        From 65-84 years
    233
        85 years and over
    13
    Age continuous
    Units: years
        median (full range (min-max))
    73 (26 to 91)
    Gender categorical
    At baseline, just over half of the patients were women (56.4%). Gender was well balanced between the treatment groups (p = 0.819).
    Units: Subjects
        Female
    176
        Male
    136
    Region
    Two thirds of patients (66.7%) were enrolled in Europe and one third (33.3%) in North America. Region was well balanced between the treatment groups.
    Units: Subjects
        North America
    104
        Europe
    208
    Race
    The large majority (96.8%) of patients were white. Race was well balanced between the treatment groups (p = 0.165).
    Units: Subjects
        White
    302
        Black or African American
    5
        Asian
    2
        Other
    2
        Unknown
    1
    Histological subtype assessed by local investigators
    The most common histological subtype assessed by local investigators was DLBCL (77.6% of patients), 13.8% of patients had DLBCL transformed from indolent, and 8.7% had follicular lymphoma (FL) Grade 3 lymphoma. No relevant difference between the treatment groups was observed for this baseline disease characteristic (p = 0.644).
    Units: Subjects
        DLBCL
    242
        DLBCL transformed from indolent
    43
        FL Grade 3
    27
    Histology assessed by CPRC
    According to Central Pathology Review Committee (CPRC), 78.5% of patients had DLBCL, 4.8% had DLBCL with follicular components and 2.6% had FL Grade 3. Other patients were not diagnosed for lymphoma (4.8%), had other lymphoma (3.8%), were not assessed (3.5%) or assessment was missing (1.9%). No relevant difference between the treatment groups was observed for this baseline disease characteristic (p = 0.388).
    Units: Subjects
        DLBCL
    245
        DLBCL with follicular components
    15
        FL Grade 3
    8
        Non-diagnostic for lymphoma
    15
        Other lymphoma (none of the above)
    12
        Not assessed
    11
        Missing
    6
    Number of prior lines of therapy for DLBCL or FL Grade 3
    Most patients had received 1 prior therapy (61.9%) for DLBCL or FL Grade 3 lymphoma; 21.8% had received 2 prior therapies and 11.5% received 3 prior therapies. No relevant difference between the treatment groups was observed for this baseline disease characteristic (p = 0.823).
    Units: Subjects
        0 prior therapy
    15
        1 prior therapy
    193
        2 prior therapies
    68
        3 prior therapies
    36
    IPI Score
    Most patients (53.2%) had a baseline IPI score ≥ 3. No relevant difference between the treatment groups was observed for this baseline disease characteristic (p = 0.285).
    Units: Subjects
        Score = 0
    2
        Score = 1
    41
        Score = 2
    103
        Score >=3
    166
    Reason for ineligibility for HDC and SCT
    Main reason for non-eligibility for high-dose chemotherapy (HDC) and stem cell transplant (SCT) was “patient is not adequately fit” (39.4%). No relevant difference between the treatment groups was observed for this baseline disease characteristic (p = 0.579).
    Units: Subjects
        Patient is not adequately fit
    123
        Patient refused
    40
        Prior transplant
    28
        Co-morbid conditions
    26
        Failure to mobilize adequate number of cells
    2
        Other
    93
    ECOG PS
    Eastern Cooperative Oncology Group performance status (ECOG PS) at baseline was 0 for 27.2% of patients, 1 for 51.6% of patients, and 2 for 20.8% of patients; the score was missing for 1 patient (0.3%). No relevant difference was observed between the treatment groups for this baseline characteristic (p = 0.735).
    Units: Subjects
        Score = 0
    85
        Score = 1
    161
        Score = 2
    65
        Missing
    1
    Number of prior systemic therapies
    The treatment groups were comparable in regards to prior NHL therapy. Overall, more than half of the patients (54.8%) received one prior systemic therapy, 24.7% received 2 prior systemic therapies and 17.6% received 3 prior systemic therapies.
    Units: Subjects
        1 therapy
    171
        2 therapies
    77
        3 therapies
    55
        4 therapies
    9
    Type of the most recent systemic therapies
    The treatment groups were comparable in regards to prior NHL therapy. For the majority of patients (87.2%) the most recent systemic therapies for NHL prior to inclusion in the study pursued a curative intent.
    Units: Subjects
        Curative
    272
        Maintenance
    23
        Palliative
    10
        Other
    7
    Best response to the most recent systemic therapy
    The treatment groups were comparable in regards to prior NHL therapy. The best response to the most recent systemic therapy was complete response (CR) or complete response unconfirmed (CRu) in 55.4% of patients and PR in 30.1%.
    Units: Subjects
        Complete response/complete response unconfirmed
    173
        Partial response
    94
        Stable disease
    21
        Progressive disease
    20
        Unknown
    4
    Medical history - cardiac history
    Most patients presented with a cardiac history at baseline: 63.9% in the pixantrone + R group and 66.2% in the gemcitabine + R group.
    Units: Subjects
        Patients with any cardiac history events
    203
        Patients with no cardiac history events
    109
    Body Mass Index (BMI)
    At baseline, the mean BMI was 27.5 kg/m^2 ranging from 15 kg/m^2 to 62 kg/m^2. No relevant difference between the treatment groups was observed for BMI (p = 0.849).
    Units: kg/m^2
        arithmetic mean (full range (min-max))
    27.5 (15 to 62)
    Time since initial diagnosis of DLBCL or FL Grade 3
    The initial diagnosis of DLBCL or FL Grade 3 was made at a median of 1.9 years (i.e. 22.8 months; ranging from 0 to 15 years) prior to study entry. No relevant difference between the treatment groups was observed for this baseline disease characteristic (p = 0.782).
    Units: years
        median (full range (min-max))
    1.9 (0 to 15)
    Time from initiation of first-line therapy for DLBCL or FL Grade 3 until first relapse
    Time from initiation of first-line therapy for DLBCL or FL grade 3 until first relapse was a median of 1.4 years (i.e. 16.8 months). For pixantrone + rituximab, n = 144; for gemcitabine + rituximab, n = 151. No relevant difference between the treatment groups was observed for this baseline disease characteristic (p = 0.778).
    Units: years
        median (full range (min-max))
    1.4 (0 to 11)

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Pixantrone + Rituximab
    Reporting group description
    Investigational therapy arm: The intent-to-treat (ITT) population included all 155 patients randomized to pixantrone + rituximab (pixantrone + R). The ITT population was used for analysis of demographic and baseline characteristics and efficacy. The safety population included all randomized patients who received at least one administration of study drug (153 patients); 2 patients were excluded from the safety population. The safety population was used for all safety analyses. 83 patients in the ITT population discontinued treatment due to: progressive disease (47), adverse event (21), consent withdrawal (6), death (5), or other reason (4).

    Reporting group title
    Gemcitabine + Rituximab
    Reporting group description
    Control therapy arm: The intent-to-treat (ITT) population included all 157 patients randomized to gemcitabine + rituximab (gemcitabine + R). The ITT population was used for analysis of demographic and baseline characteristics and efficacy. The safety population included all randomized patients who received at least one administration of study drug (149 patients); 8 patients were excluded from the safety population. The safety population was used for all safety analyses. 96 patients discontinued treatment due to: progressive disease (50), adverse event (15), consent withdrawal (16), death (10), or other reason (5).

    Subject analysis set title
    ITT population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population was defined as all randomized patients regardless of whether patients received any study treatment, or received a different treatment from the treatment they were randomized to. Patients were analyzed according to the treatment to which they were assigned at randomization. The ITT population consisted of all 312 patients randomized.

    Primary: Progression-free Survival (PFS) per IRC assessment in the ITT population

    Close Top of page
    End point title
    Progression-free Survival (PFS) per IRC assessment in the ITT population
    End point description
    The primary efficacy endpoint was progression-free survival (PFS), defined as the time from the date of randomization to the date of progressive disease (PD) or death due to any cause (whichever occurred first). The primary analysis of PFS was based on disease progression as determined by the Independent Radiology Committee (IRC). Median PFS and the corresponding 95% CI were estimated using the Kaplan-Meier method and were presented by treatment arm. The Kaplan-Meier curve was plotted.
    End point type
    Primary
    End point timeframe
    Disease was assessed at baseline and during treatment (up to six 28-day cycles), early follow-up (6 months), & intermediate follow-up (18 months) periods. Survival was assessed during early follow-up, intermediate follow-up, & survival follow-up periods.
    End point values
    Pixantrone + Rituximab Gemcitabine + Rituximab
    Number of subjects analysed
    155
    157
    Units: Months
        median (confidence interval 95%)
    7.3 (5.2 to 8.4)
    6.3 (4.4 to 8.1)
    Attachments
    Kaplan-Meier Curve of PFS in ITT
    Statistical analysis title
    Treatment difference in PFS
    Statistical analysis description
    PFS was compared between the 2 treatment arms in the ITT population using a stratified log-rank test adjusted for randomization stratification factors (number of prior therapies/International Prognostic Index [IPI]/time from start of 1st line therapy to 1st relapse). The adjusted hazard ratio and 95% CI were calculated using the Cox proportional hazards model adjusted for randomization stratification factors.
    Comparison groups
    Pixantrone + Rituximab v Gemcitabine + Rituximab
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2782
    Method
    Stratified log-rank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    1.14

    Secondary: Overall Survival (OS) in the ITT Population (Interim Results)

    Close Top of page
    End point title
    Overall Survival (OS) in the ITT Population (Interim Results)
    End point description
    Overall survival (OS) was defined as the time from the date of randomization to the date of death due to any cause. If a patient was alive or the survival status was unknown by the data cut-off date for analysis, survival was censored at the last date the patient was known to be alive. The following analysis of OS is the first interim analysis planned by the protocol, which was carried out at the time of the core database lock. At the time of the first interim analysis, 177 deaths had occurred: 94 (60.6%) in the pixantrone + R group and 83 (52.9%) in the gemcitabine + R group. Median OS and the corresponding 95% CI were estimated using the Kaplan-Meier method and were presented by treatment arm. The Kaplan-Meier curve was plotted.
    End point type
    Secondary
    End point timeframe
    Disease was assessed at baseline and during treatment (up to six 28-day cycles), early follow-up (6 months), & intermediate follow-up (18 months) periods. Survival was assessed during early follow-up, intermediate follow-up, & survival follow-up periods.
    End point values
    Pixantrone + Rituximab Gemcitabine + Rituximab
    Number of subjects analysed
    155
    157
    Units: Months
        median (confidence interval 95%)
    13.3 (10.1 to 19.8)
    19.6 (12.4 to 31.9)
    Attachments
    Kaplan-Meier Curve of OS in ITT
    Statistical analysis title
    Treatment difference in OS
    Statistical analysis description
    OS was compared between the 2 treatment arms in the ITT population using a stratified log-rank test adjusted for randomization stratification factors (number of prior therapies/IPI/time from start of 1st line therapy to 1st relapse). The adjusted hazard ratio and 95% CI were calculated using the Cox proportional hazards model adjusted for randomization stratification factors.
    Comparison groups
    Pixantrone + Rituximab v Gemcitabine + Rituximab
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4326
    Method
    Stratified log-rank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.53

    Secondary: Overall Response Rate (ORR) per IRC assessment in the ITT Population

    Close Top of page
    End point title
    Overall Response Rate (ORR) per IRC assessment in the ITT Population
    End point description
    The Overall Response Rate (ORR) was defined as the proportion of patients who achieved a Complete Response (CR) or Partial Response (PR) without additional anticancer therapy. Patients who discontinued before any response was observed or received additional anticancer therapy before a response, were considered non-responders. The 95% CI for ORR in each treatment arm was calculated using the Clopper-Pearson method.
    End point type
    Secondary
    End point timeframe
    Disease was assessed at baseline and during treatment (up to six 28-day cycles), early follow-up (6 months), & intermediate follow-up (18 months) periods. Survival was assessed during early follow-up, intermediate follow-up, & survival follow-up periods.
    End point values
    Pixantrone + Rituximab Gemcitabine + Rituximab
    Number of subjects analysed
    155
    157
    Units: Percent
        number (confidence interval 95%)
    61.9 (53.8 to 69.6)
    43.9 (36.0 to 52.1)
    Statistical analysis title
    Treatment difference in ORR estimate
    Statistical analysis description
    ORR was compared between the 2 treatment arms in the ITT population using the Cochran-Mantel-Haenszel test, adjusted for randomization stratification factors (number of prior therapies/IPI/time from start of 1st line therapy to 1st relapse). The 95% CI for the difference in ORR between the 2 treatment arms was based on the Agresti-Caffo method.
    Comparison groups
    Pixantrone + Rituximab v Gemcitabine + Rituximab
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment difference in ORR estimate
    Point estimate
    18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.9
         upper limit
    28.6

    Secondary: Complete Response (CR) per IRC assessment in the ITT population

    Close Top of page
    End point title
    Complete Response (CR) per IRC assessment in the ITT population
    End point description
    The Complete Response (CR) rate was defined as the proportion of patients who achieved a CR without additional therapy. Patients who discontinued or received additional anticancer therapy before any response had been observed were considered non-responders. The 95% CI for CR in each treatment arm was calculated using the Clopper-Pearson method.
    End point type
    Secondary
    End point timeframe
    Disease was assessed at baseline and during treatment (up to six 28-day cycles), early follow-up (6 months), & intermediate follow-up (18 months) periods. Survival was assessed during early follow-up, intermediate follow-up, & survival follow-up periods.
    End point values
    Pixantrone + Rituximab Gemcitabine + Rituximab
    Number of subjects analysed
    155
    157
    Units: Percent
        number (confidence interval 95%)
    35.5 (28.0 to 43.6)
    21.7 (15.5 to 28.9)
    Statistical analysis title
    Treatment difference in CR estimate
    Statistical analysis description
    CR was compared between the 2 treatment arms in the ITT population using the Cochran-Mantel-Haenszel test, adjusted for randomization stratification factors (number of prior therapies/IPI/time from start of 1st line therapy to 1st relapse). The 95% CI for the difference in CR between the 2 treatment arms was based on the Agresti-Caffo method.
    Comparison groups
    Pixantrone + Rituximab v Gemcitabine + Rituximab
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0047
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment difference in CR estimate
    Point estimate
    13.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.8
         upper limit
    23.5

    Other pre-specified: Duration of Overall Response (DOR) per IRC assessment in the ITT population

    Close Top of page
    End point title
    Duration of Overall Response (DOR) per IRC assessment in the ITT population
    End point description
    Duration of Overall Response (DOR) was only defined for CR or PR responders. DOR was calculated as the time from the date of the first documented CR or PR to the date of first documented evidence of PD (or relapse for patients who experienced a CR on this study) or death from any cause. Median DOR and the corresponding 95% CI were estimated using the Kaplan-Meier method and were presented by treatment arm.
    End point type
    Other pre-specified
    End point timeframe
    Disease was assessed at baseline and during treatment (up to six 28-day cycles), early follow-up (6 months), & intermediate follow-up (18 months) periods. Survival was assessed during early follow-up, intermediate follow-up, & survival follow-up periods.
    End point values
    Pixantrone + Rituximab Gemcitabine + Rituximab
    Number of subjects analysed
    155
    157
    Units: Months
        median (confidence interval 95%)
    10.0 (6.6 to 17.3)
    9.1 (6.5 to 18.5)
    Statistical analysis title
    Treatment difference in DOR
    Statistical analysis description
    DOR was compared between the 2 treatment arms in the ITT population using an unstratified log-rank test. The estimated hazard ratio and 95% CI were calculated using the Cox proportional hazard model adjusted for randomization stratification factors (number of prior therapies/IPI/time from start of 1st line therapy to 1st relapse).
    Comparison groups
    Pixantrone + Rituximab v Gemcitabine + Rituximab
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8563
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.63
         upper limit
    1.47

    Other pre-specified: Duration of Complete Response (DCR) per IRC assessment in the ITT population

    Close Top of page
    End point title
    Duration of Complete Response (DCR) per IRC assessment in the ITT population
    End point description
    Duration of Complete Response (DCR) was defined as the time from the date of the first documented CR to the first documented tumor relapse or death due to any cause. Median DCR and the corresponding 95% CI were estimated using the Kaplan-Meier method and were presented by treatment arm. Kaplan-Meier estimate of median DCR, months [95% CI]: Pixantrone + R: 13.0 [7.1, 30.7] Gemcitabine + R: 15.4 [7.5, non-estimable]
    End point type
    Other pre-specified
    End point timeframe
    Disease was assessed at baseline and during treatment (up to six 28-day cycles), early follow-up (6 months), & intermediate follow-up (18 months) periods. Survival was assessed during early follow-up, intermediate follow-up, & survival follow-up period.
    End point values
    Pixantrone + Rituximab Gemcitabine + Rituximab
    Number of subjects analysed
    155
    157
    Units: Months
        number (confidence interval 95%)
    13.0 (7.1 to 30.7)
    15.4 (7.5 to 9999.9)
    Statistical analysis title
    Treatment difference in DCR
    Statistical analysis description
    DCR was compared between the 2 treatment arms in the ITT population using a log-rank test. The estimated hazard ratio and 95% CI were calculated using the Cox proportional hazards model adjusted for randomization stratification factors.
    Comparison groups
    Pixantrone + Rituximab v Gemcitabine + Rituximab
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9374
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.56
         upper limit
    1.88

    Other pre-specified: Patients who received Stem Cell Transplant (SCT) after start of study treatment in the ITT population

    Close Top of page
    End point title
    Patients who received Stem Cell Transplant (SCT) after start of study treatment in the ITT population
    End point description
    The proportion of patients who received a stem cell transplant (SCT) was defined as the percentage of all randomized patients in the ITT population who received a SCT after start of study treatment. The 95% CI for SCT in each treatment arm was calculated using the Clopper-Pearson method.
    End point type
    Other pre-specified
    End point timeframe
    After start of study treatment and through the treatment period (up to six 28-day cycles), early follow-up (6 months) period, intermediate follow-up (18 months) period, and survival follow-up period.
    End point values
    Pixantrone + Rituximab Gemcitabine + Rituximab
    Number of subjects analysed
    155
    157
    Units: percent
        number (confidence interval 95%)
    2.6 (0.7 to 6.5)
    1.3 (0.2 to 4.5)
    Statistical analysis title
    Treatment difference in SCT estimate
    Statistical analysis description
    SCT was compared between the 2 treatment arms in the ITT population using the Cochran-Mantel-Haenszel test, adjusted for randomization stratification factors (number of prior therapies/IPI/time from start of 1st line therapy to 1st relapse). The 95% CI for the difference in SCT between the 2 treatment arms was based on the Agresti-Caffo method.
    Comparison groups
    Pixantrone + Rituximab v Gemcitabine + Rituximab
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4015
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Treatment difference in SCT estimate
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.2
         upper limit
    4.8

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    For randomized patients, from signing of informed consent. For nonrandomized screen failures, SAEs from signing of informed consent to time of screen failure.
    Adverse event reporting additional description
    Adverse events could have been spontaneously reported or elicited during open-ended questioning, examination or evaluation of the patient. Subjects who experienced multiple events within the same preferred term (PT) were counted once per PT at the highest severity grade.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Pixantrone + Rituximab
    Reporting group description
    Treatment -emergent adverse events (TEAEs) for patients who received pixantrone + R are reported. Serious TEAEs that occurred in 2 or more patients in either treatment arm and all serious TEAEs leading to death are reported. Non-serious TEAEs that occurred in 10% or more of patients in either treatment arm are reported.

    Reporting group title
    Gemcitabine + Rituximab
    Reporting group description
    Treatment -emergent adverse events (TEAEs) for patients who received gemcitabine + R are reported. Serious TEAEs that occurred in 2 or more patients in either treatment arm and all serious TEAEs leading to death are reported. Non-serious TEAEs that occurred in 10% or more of patients in either treatment arm are reported.

    Serious adverse events
    Pixantrone + Rituximab Gemcitabine + Rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    59 / 153 (38.56%)
    57 / 149 (38.26%)
         number of deaths (all causes)
    93
    81
         number of deaths resulting from adverse events
    14
    8
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Myelodysplastic syndrome
         subjects affected / exposed
    3 / 153 (1.96%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Disseminated large cell lymphoma
    Additional description: This serious TEAE occurred in 1 patient in the pixantrone + R arm and it led to death.
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    3 / 153 (1.96%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Atrial fibrillation
         subjects affected / exposed
    2 / 153 (1.31%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cytotoxic cardiomyopathy
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 153 (0.00%)
    3 / 149 (2.01%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    2 / 3
    Cardiac failure congestive
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 153 (1.31%)
    3 / 149 (2.01%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 153 (0.65%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
    Additional description: This serious TEAE occurred in 1 patient in the gemcitabine + R arm and it led to death.
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 153 (3.27%)
    8 / 149 (5.37%)
         occurrences causally related to treatment / all
    5 / 5
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    5 / 153 (3.27%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 153 (1.31%)
    3 / 149 (2.01%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    3 / 153 (1.96%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 153 (2.61%)
    8 / 149 (5.37%)
         occurrences causally related to treatment / all
    1 / 4
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 153 (1.31%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 153 (1.31%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalized oedema
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
    Additional description: This serious TEAE occurred in 1 patient in each treatment arm. This serious TEAE in the pixantrone + R arm led to death.
         subjects affected / exposed
    1 / 153 (0.65%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Multi-organ failure
    Additional description: This serious TEAE occurred in 1 patient in the pixantrone + R arm and it led to death.
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 153 (0.65%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    2 / 153 (1.31%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hydronephrosis
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis haemorrhagic
    Additional description: This serious TEAE occurred in 1 patient in the pixantrone + R arm and it led to death. This patient also experienced cerebrovascular accident (serious TEAE, related to treatment, fatal).
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 153 (1.31%)
    3 / 149 (2.01%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
    Additional description: This serious TEAE occurred in 1 patient in the pixantrone + R arm and it led to death.
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    8 / 153 (5.23%)
    4 / 149 (2.68%)
         occurrences causally related to treatment / all
    3 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 153 (1.31%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Septic shock
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 153 (1.31%)
    3 / 149 (2.01%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 153 (0.65%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 153 (0.00%)
    3 / 149 (2.01%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Pixantrone + Rituximab Gemcitabine + Rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    149 / 153 (97.39%)
    146 / 149 (97.99%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    17 / 153 (11.11%)
    6 / 149 (4.03%)
         occurrences all number
    17
    6
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    19 / 153 (12.42%)
    13 / 149 (8.72%)
         occurrences all number
    19
    13
    Cough
         subjects affected / exposed
    19 / 153 (12.42%)
    19 / 149 (12.75%)
         occurrences all number
    19
    19
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    106 / 153 (69.28%)
    88 / 149 (59.06%)
         occurrences all number
    106
    88
    Anaemia
         subjects affected / exposed
    42 / 153 (27.45%)
    74 / 149 (49.66%)
         occurrences all number
    42
    74
    Thrombocytopenia
         subjects affected / exposed
    25 / 153 (16.34%)
    98 / 149 (65.77%)
         occurrences all number
    25
    98
    Leukopenia
         subjects affected / exposed
    12 / 153 (7.84%)
    19 / 149 (12.75%)
         occurrences all number
    12
    19
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    45 / 153 (29.41%)
    34 / 149 (22.82%)
         occurrences all number
    45
    34
    Pyrexia
         subjects affected / exposed
    21 / 153 (13.73%)
    35 / 149 (23.49%)
         occurrences all number
    21
    35
    Asthenia
         subjects affected / exposed
    20 / 153 (13.07%)
    18 / 149 (12.08%)
         occurrences all number
    20
    18
    Oedema peripheral
         subjects affected / exposed
    19 / 153 (12.42%)
    31 / 149 (20.81%)
         occurrences all number
    19
    31
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    38 / 153 (24.84%)
    24 / 149 (16.11%)
         occurrences all number
    38
    24
    Constipation
         subjects affected / exposed
    35 / 153 (22.88%)
    20 / 149 (13.42%)
         occurrences all number
    35
    20
    Diarrhoea
         subjects affected / exposed
    24 / 153 (15.69%)
    20 / 149 (13.42%)
         occurrences all number
    24
    20
    Vomiting
         subjects affected / exposed
    21 / 153 (13.73%)
    17 / 149 (11.41%)
         occurrences all number
    21
    17
    Stomatitis
         subjects affected / exposed
    16 / 153 (10.46%)
    10 / 149 (6.71%)
         occurrences all number
    16
    10
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    29 / 153 (18.95%)
    2 / 149 (1.34%)
         occurrences all number
    29
    2
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    28 / 153 (18.30%)
    15 / 149 (10.07%)
         occurrences all number
    28
    15

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Dec 2010
    Protocol Amendment 1 concerned the clarification of PFS definition and the modification of censoring rules. For patients “who received any new lymphoma-directed therapy (other than rituximab as maintenance) before progression of disease”, the date of censoring was defined as the date of the “last radiologic assessment prior to the start of the new therapy”, instead of the “date of first administration of additional treatment”.
    10 Mar 2011
    Protocol Amendment 2 concerned mainly: - The change in the study primary objective: OS, initially a secondary objective, was added to PFS as a combined primary objective. Statistical methods including sample size determination were updated taking into account this modification. - The increase in the number of patients to be randomized (from 300 to 350). - The replacement of the stratification factor “prior SCT” by “length of time from initiation of first-line therapy for aggressive NHL until first relapse”. - The addition of safety criteria (study-related AEs and some cardiac events and assessments) during the Follow-up periods. - As regards to the reporting of AEs, it was also specified that cardiac AEs ≥ grade 3 were to be collected until the end of the study and followed until resolution or no further improvement was expected. - Specifications on clinical examination were added. - The modification of inclusion criteria (bone core biopsy was to be obtained within 8 weeks prior to randomization, addition of the necessity to confirm the response to CHOP-R by a second radiographic assessment; removal of the 24-week delay between day 1 of last cycle of CHOP-R or equivalent treatment and subsequent relapse, and update of the laboratory requirements for platelets and absolute neutrophil count). - The addition of primary refractory aggressive NHL as an exclusion criterion. - An update of pixantrone and gemcitabine dose adjustments and delays for hematologic toxicity. - Specifications for low-dose corticosteroids use as concomitant medication. - For the selection of target lesions, measurable lesions in a previously radiated site could not be considered target lesions. - Wording specifications. - Procedures specifications.
    03 Aug 2011
    Protocol Amendment 3 included: - An update of Safety information in the background section. - The clarification of the use of the terms “NHL” and “DLBCL”. - The modification of inclusion criteria: bone marrow biopsy criteria were clarified, prior CHOP-R was allowed for any type of NHL, patients with transformed follicular lymphoma who may not have received CHOP-R as first-line therapy for aggressive NHL could also be included in the study, definition of measurable disease was adjusted to be consistent with other Sections in the protocol, and it was specified that DLBCL diagnosis was to be confirmed by pathologic review. - The modification of exclusion criteria: definitions of measurable disease and primary refractory disease were updated and clarified, CNS involvement was further detailed, and enrolment of patients who had had certain low-risk cancers commonly found in this population was finally allowed. - Disease Assessment Criteria were extensively clarified. - PET scan requirements were modified. - The prior requirement for central evaluation of echocardiograms was removed, since implementing the central read processes negatively impacted timely site initiation and accrual of patients. There was no clear need for a retrospective central read, but there was considerable negative impact; therefore, central read was deleted. Local echo evaluations were used for safety and treatment decisions. - The timing of IDMC meetings was clarified. - A recommendation was added that rituximab be administered first, and the section regarding drugs administration was reorganized to allow investigators more clearly identifying potential rituximab-related adverse reactions. The window for pixantrone administration was clarified. - The requirement for physical examinations before study drug administration was clarified. - Procedures for dose adjustments and delays were detailed. - Safety reporting was clarified and revised. - Pathology procedures were clarified.
    05 Jan 2012
    Protocol Amendment 4 aimed to: - Change the primary endpoint of the study to “overall survival” only, following FDA recommendations. PFS was therefore a secondary objective. All the protocol (primary and secondary endpoints, statistical analyses, etc) was modified accordingly. - An interim analysis of OS, to be done when 150 deaths (50%) had occurred, was planned. The final OS analysis was to be performed when 300 deaths had occurred. - Stratification factors were adjusted. - Criteria for eligible patients were modified and clarified to ensure safety and enrolment of the target population. - Bone marrow biopsy requirements were revised. - Troponin sample requirements and processing were clarified. - Dose adjustments and delays for toxicity were detailed. - Follow-up for randomized patients versus not randomized patients was clarified. - The definition of measurable disease was slightly revised. - PET scan requirements were clarified.
    09 Apr 2012
    Protocol Amendment 5, for North America (NA), concerned: - For the primary objective, eligibility of patients was further detailed: patients were to “have no progression for at least 12 weeks after last dose of a treatment regimen” instead of “were to have had a response to prior therapy”. - In response to a recommendation from the EMA, pixantrone dose was expressed in its base form (instead of its salt form) in the whole document. - It was specified that the study would be conducted in the United States, Canada, Eastern and Western Europe and South America. - Requirements for entering Survival Follow-up period were updated. - The formula to calculate doxorubicin equivalent dose was replaced. - Wording specifications. - Procedures specifications.
    18 Jun 2012
    Protocol Amendment 5 NNA, for Non-North America (NNA), included: - The rationale for rituximab-pixantrone combination was further detailed (NA + NNA). - It was specified that the study would be conducted in NA, Western Europe and potentially Eastern Europe (NNA). - It was specified that the study would be conducted in NA, Western Europe and Eastern Europe for (NA). - Inclusion criterion on contraceptive methods to be used was updated (NA + NNA). - Possible adverse reactions associated with rituximab were added and concerned cytokine release syndrome, hypersensitivity reactions and anaphylaxis and progressive multifocal leukoencephalopathy (NA + NNA). - Recommendations were given on the use of some concomitant medications (especially those metabolized by CYP1A2) when co-administered with pixantrone (NA + NNA). - In response to EMA, the pixantrone dose was expressed in its base form (instead of its salt form) in the whole document (NA).
    31 Aug 2012
    Protocol Amendment 6, for North America (NA) included: - The rationale for rituximab-pixantrone combination was further detailed (NA + NNA). - It was specified that the study would be conducted in NA, Western Europe and potentially Eastern Europe (NNA). - It was specified that the study would be conducted in NA, Western Europe and Eastern Europe for (NA). - Inclusion criterion on contraceptive methods to be used was updated (NA + NNA). - Possible adverse reactions associated with rituximab were added and concerned cytokine release syndrome, hypersensitivity reactions and anaphylaxis and progressive multifocal leukoencephalopathy (NA + NNA). - Recommendations were given on the use of some concomitant medications (especially those metabolized by CYP1A2) when co-administered with pixantrone (NA + NNA). - In response to EMA, the pixantrone dose was expressed in its base form (instead of its salt form) in the whole document (NA).
    17 Oct 2012
    Protocol Amendment 6 NNA, for Non-North America (NNA), concerned mainly: - In response to EMA, the pixantrone dose was expressed in its base form (instead of its salt form) in the whole document. - It was specified that the study would be conducted in NA, Eastern and Western Europe. - Procedures for reporting AEs updated.
    16 Sep 2013
    Protocol Amendment 7 NNA, for Non-North America (NNA), and aimed to: - Entirely revise the synopsis consistently with the protocol body: several sections were added (No. of study, Name of sponsor, Phase of development, Investigational Drug, Duration of Study and Treatment, Planned No. of Patients, Test Product and Reference therapy, Treatment regimen, Inclusion and Exclusion criteria, Schedule of treatment and assessments, Criteria for evaluation (renamed section title). - Change in EOT window: The EOT visit was to occur at 4 to 7 weeks after last study drug dose, inclusive, or before non-protocol NHL therapy was given, whichever occurred first instead of “the EOT visit occurs at 5 weeks ± 1week after the last study drug administration or before non-protocol NHL therapy is given”. - Gemcitabine dose modifications for hematologic toxicity were completed. - Gemcitabine and pixantrone dose modifications for non-hematologic toxicity were completed. - Concomitant medications were updated: additional recommendations for drug’s photosensitivity. - Use of local laboratories for urgent clinical decisions: Local labs were required, as needed, for time-limited evaluation windows, per protocol, and to support urgent clinical decisions. - Details were added for the description of visits schedules and assessments (for the screening period, the End of treatment visit, and Follow-up periods). - The description of disease assessment was also modified (in case no EOT PET scan could be obtained, for bone marrow biopsy…). - Specification on AEs and AEs reporting were added. - Some minor revisions and wording specifications were implemented.
    25 Jul 2014
    Protocol Amendment 8, for NA and NNA, unified previous NA and NAA versions. Major changes were: - Primary endpoint (previously OS) was replaced by PFS. - Number of subjects to be randomized was decreased from 350 to 260 patients. Enrolment was to be continued until 195 PFS events occurred, or approximately 260 patients were enrolled, whichever occurred first. Enrolment period was planned approximately 60 months from study initiation. - It was specified that no interim analysis of PFS was planned. - Added exploratory objectives (assessment of DOR and DCR between treatments, proportion of patients who received a SCT after study treatment). - Rituximab given as maintenance therapy was not allowed prior to the EOT visit per protocol window. - Added precisions for patients entering Follow-up periods. - Added definition of EOS (i.e. date when the required OS events have occurred or the study is terminated). - Criteria for efficacy evaluation were further detailed. - Consequently to the change in the objectives and primary criteria, statistical methods were adapted, including the sample size re-estimation. - Updated pixantrone safety in clinical study in the background and rationale. - Precisions were given for patients still on treatment at the end of recruitment (to continue per protocol until EOT and enter the survival follow-up or directly to enter the survival follow-up period). - Added details for completion and discontinuation of treatment. - Added information about pixantrone handling, preparation, administration and storage. - Added recommendations for drug’s for drug’s photosensitivity. - Visit schedule and assessments as well as imaging ad criteria for response, were further detailed. - Updated definition and reporting of AEs. - Added length of time from initiation of therapy for DLBCL or FL grade 3 until first relapse to subgroup analyses. - Added informed consent for collecting survival information. - Added PK study.
    10 Jul 2017
    Protocol Amendment 9 aimed to: - Updated the total number of patients to be enrolled, after simulation performed by the sponsor, from 260 to 320 patients, to reach the 195 PFS events (per IRC) within a reasonable timeline to meet the study report due date. - Increased enrolment period from 60 to 80 months, to accommodate the increase in the number of planned patients’ enrolment. - Added one additional interim analysis for secondary efficacy endpoint OS, i.e. when 190 OS events (86% of the required number of OS events) have occurred, due to much slower occurrence of OS events than expected. Indeed, based on the updated projection, the time to achieve 220 OS events is year 2022, more than 3 years from the first interim analysis. Adding the 2nd OS interim analysis would provide a chance to stop the trial earlier if the treatment demonstrated superior survival benefit. - The hierarchy order for testing the secondary efficacy endpoints was updated. In view of the importance of OS in these patients and in order to better match the study objectives, there was reorganization of the order of endpoints testing, to put OS ahead of overall response and CR, in the hypothesis testing hierarchy of secondary endpoints. - Clarified treatment blinding. - Added a sub-group analysis. As the current indication is in 3rd and 4th line, a subgroup analysis defined by 0-1 line versus more than 2 lines was added to confirm the efficacy and safety of pixantrone in the current indication and to evaluate them in 2nd line.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Following the analysis of the primary endpoint of this study, it was decided by the Sponsor not to continue the study until the target 220 events for the OS analysis, but terminate it within 6 months of the data cut-off date (14 Sep 2018).
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA